Tamoxifen: Gene Test May Predict Benefit

Action Points

In high-risk women, breast cancer can be prevented by treatment with selective estrogen receptor modulators, drugs that compete with estrogens for binding to the estrogen receptor. Five years of therapy with tamoxifen or raloxifene can reduce the occurrence of breast cancer in these women by approximately one-half.

This study observed SNPs in the ZNF423 gene on chromosome 16 and SNPs on chromosome 4 near the CTSO gene that were associated with alterations in risk for breast cancer during treatment with tamoxifen or raloxifene.

Two genes may predict which women would benefit from breast cancer primary prevention with tamoxifen or raloxifene (Evista), analysis of the pivotal trials showed.

Carrying both unfavorable alleles for ZNF423 and CTSO on a selective estrogen receptor modulator (SERM) predicted a 5.7-fold difference in breast cancer risk compared with carrying neither, James N. Ingle, MD, of the Mayo Clinic in Rochester, Minn., and colleagues found.

By comparison, the overall benefit in the National Surgical Adjuvant Breast and Bowel Project P-1 trial of tamoxifen and P-2, or STAR, trial of raloxifene was about a 50% reduction in risk.

The ZNF423 risk allele appeared to induce expression of the breast cancer risk gene BRCA1 in the presence of estrogen regardless of raloxifene or tamoxifen treatment, whereas the wild-type genotype didn't respond to estrogen when either drug was around, the group reported online in Cancer Discovery.

The same pattern was seen in cell line tests with the CTSO gene except that the lower response came with the variant instead of wild-type CTSO.

If confirmed prospectively, women without the gene variants could be spared potential side effects from treatments that would offer them little to no benefit, and women with the variants could be reassured that they likely are benefiting, the researchers suggested.

The relatively high number needed to treat for 5 years to prevent one breast cancer (51) and rare but serious adverse events, such as pulmonary embolism and endometrial cancer, have led to low uptake of the prevention strategy, they noted.

Utilization would likely increase if the drugs could be better targeted, Therese Bevers, MD, medical director of the Cancer Prevention Center at MD Anderson in Houston, predicted in an interview with MedPage Today.

"We've always said one size does not fit all," she said. "However, in regard to breast cancer risk reduction therapy with tamoxifen or raloxifene, we haven't really been able to tailor therapy to individual women because we didn't have specific biological factors that would indicate which women would respond to therapy."

The next step will be clinical trials to show impact of SERMS in the genetically-targeted population, she noted.

While BRCA1 mutations predict elevated breast cancer risk, women with the mutation haven't been shown to benefit from tamoxifen or raloxifene in prevention, Bevers pointed out.

The researchers ran a nested case-control genome-wide association study to search for single-nucleotide polymorphisms among the 592 women who developed breast cancer while on SERM therapy compared with 1,171 matched controls among the 33,000 participants in the two trials.

They then ran an analysis on the case-control cohort for odds ratios associated with the ZNF423 and CTSO gene alleles, which no prior reports had tied to SERM effects, to estrogens, or to breast cancer risk.

The fact that both were associated with altered expression of BRCA1 "enhanced confidence in the validity of the observed associations," the researchers pointed out.

The study was supported in part by NIH grants and the RIKEN Center for Genomic Medicine and the Biobank Japan Project funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan.

The researchers reported having no conflicts of interest to disclose.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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